Chemistry Letters Vol.35, No.4 (2006)
457
Table 2. N-Alkylations of sulfonamides with alkyl diphenyl-
phosphinites in the presence of methyl acrylate,a DBBQ,b or tri-
methylsilylmethyl azidec
Y
X
H
N
Ph POR
Ph
Ph
OR
2
P
OMe
OMe
1
2
1
2
1
2
NsNHR (1.0 equiv.)
Oxidant
R
R
R
R
R
R
Ph PCl
2
O
O
OH
OPPh
RNNs
2
1
1.1 equiv.
X
Y
d
Entry
Phosphinite
NsNHR
Oxidant
Yield/%
% ee
N
R
O
P
e
X
1
2
3
NsNHBoc
MA
83
77
44
72
46
59
94
91
43
67
43
98
98
97
96
92
95
98
99
98
97
93
Ph
Ph
O
OMe
R
N
+
P
OMe
Ph
DBBQ
Y
OPPh
Ph
2
O
TMSCH N
2
3
3
3
3
O
2
4
5
NsNH
MA
2
DBBQ
Scheme 2.
6
TMSCH N
2
with NsNHBoc8 was further studied under various conditions so
as to improve the enantiomeric excess (Table 3). As a result, it
was found that the desired product was obtained with 95% ee
if the reaction was carried out in benzene or toluene (Entries 5
and 6). Interestingly, the same result was also obtained if the
reaction was carried out in the absence of solvent at ꢁ10 ꢂC
(Entry 8).
A proposed reaction mechanism is shown in Scheme 2: An
alkyl diphenylphosphinite reacts initially with methyl acrylate to
form adduct 1 which is in turn transformed to the phosphonium
salt 2 by the interaction with an amide. An attack of thus formed
amide anion to the carbon atom adjacent to an oxygen atom of
the alkoxy group affords the corresponding amide along with
methyl 3-diphenylphosphinoylpropionate (3).9,10
Thus, it is noted that a simple and easily available methyl
acrylate was efficient to work as an oxidant in the preparation
of N-alkylated compounds from alkyl diphenylphosphinites
and weakly acidic compounds having a nitrogen–hydrogen
bond. Further study on this type of condensation reaction is
now in progress.
7
NsNHBoc
MA
Ph
8
DBBQ
OPPh
2
9
TMSCH N
2
10
11
NsNH
MA
2
DBBQ
12
13
14
15
16
17
18
TMSCH N
65
85
82
54
52
32
51
96
84
71
90
72
59
73
2
3
3
3
NsNHBoc
MA
DBBQ
Ph
OPPh
2
TMSCH N
2
f
NsNH
MA
DBBQ
2
TMSCH N
2
aMA (2.0 equiv.), CH2Cl2 (1.2 M), rt, 24 h. bDBBQ (1.1 equiv.),
CH2Cl2 (1.2 M), rt, 1 h. cTMSCH2N3 (1.1 equiv.), 1,2-dichloropro-
pane (0.6 M), 80 ꢂC, 6 h. dDAICEL CHIRALPAK AD–H column
was used for HPLC analysis. eEe was measured after deprotection
f
of Boc group. DAICEL CHIRALPAK AS–H column was used for
HPLC analysis.
16–20). Thus, it is noted that the methyl acrylate is the most
effective oxidant in this reaction.
Next, in order to confirm the usefulness of methyl acrylate,
reactions of 2-nitrobenzenesulfonamides6 with alkyl diphenyl-
phosphinites derived from chiral secondary alcohols were exam-
ined. The results are summarized in Table 2. For comparison, the
results obtained with DBBQ and trimethylsilylmethyl azide are
also listed.7
This study was supported in part by the Grant of the 21st
Century COE Program, Ministry of Education, Culture, Sports,
Science and Technology (MEXT), Japan.
References and Notes
Results shown in Table 2 demonstrate clearly that the
methyl acrylate gives better yields than any other oxidants. Good
enantiomeric excess was attained by using methyl acrylate
especially in the cases with (S)-sec-butyl diphenylphosphinite
and (R)-1-methyl-3-phenylpropyl diphenylphosphinite, while a
slightly lower enantiomeric excess was recorded in Entry 13
than that obtained with trimethylsilylmethyl azide (Entry 15).
Then, the reaction of (R)-1-phenylethyl diphenylphosphinite
1
For the preparation of alkyl diphenylphosphinites, See: K. Ikegai, W.
Pluempanupat, T. Mukaiyama, Chem. Lett. 2005, 34, 638.
T. Mukaiyama, H. Aoki, Chem. Lett. 2005, 34, 142.
H. Aoki, K. Kuroda, T. Mukaiyama, Chem. Lett. 2005, 34, 1266.
T. Mukaiyama, K. Kuroda, H. Aoki, Chem. Lett. 2005, 34, 1644.
R. G. Harvey, Tetrahedron 1966, 22, 2251.
T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373.
General experimental procedure is as follows: To a stirred solution of an
amide (0.3 mmol) and an alkyl diphenylphosphinite (0.33 mmol) in
dichloromethane (0.25 mL) was added methyl acrylate (0.6 mmol) at
room temperature under argon atmosphere. The reaction mixture was
stirred for 24 h at room temperature. After completion of the reaction
(detected by TLC), it was purified by preparative TLC to afford the
corresponding N-alkyl amide.
2
3
4
5
6
7
Table 3. The reaction of NsNHBoc with (R)-1-phenylethyl di-
phenylphosphinite using methyl acrylate
Ph
Ph
NsNBoc
MA (2.0 equiv.)
Solv., rt, 24 h
NsNHBoc
+
8
9
T. Fukuyama, M. Cheung, T. Kan, Synlett 1999, 1301.
OPPh2
(1.1 equiv.)
Spectral data for 3; IR (ATR, cmꢁ1) 3055, 2948, 1742, 1436, 1239,
1174, 1166, 742, 694, 533, 507, 449, 427; 1H NMR (270 MHz, CDCl3)
ꢂ7.78–7.71 (m, 4H), 7.57–7.44 (m, 6H), 3.63 (s, 3H), 2.70–2.55 (m, 4H);
13C NMR (68 MHz, CDCl3) ꢂ172.6 (d, J ¼ 16:8 Hz), 132.1 (d, J ¼
99:5 Hz), 131.8 (d, J ¼ 2:8 Hz), 130.6 (d, J ¼ 9:5 Hz ), 128.6 (d, J ¼
11:7 Hz), 52.0, 26.3 (d, J ¼ 2:2 Hz), 25.1 (d, J ¼ 72:7 Hz); HRMS
(APCIþ) calcd for C16H18O3P [M + H]þ 289.0994, found m/z
289.0990.
Entry Solvent Yield /% % ee
Entry Solvent Yield /% % ee
1
2
3
4
CH2Cl2
CHCl3
THF
85
87
71
84
91
84
89
5
6
7a
8a,b
Benzene
Toluene
None
85
81
88
88
95
95
93
95
1,4-Dioxane 84
None
a12.0 equiv. of methyl acrylate was used. bThe reaction was carried out
at ꢁ10 ꢂC.
10 A. Bell, A. H. Davidson, C. Earnshaw, H. K. Norrish, R. S. Torr, D. B.
Trowbridge, S. Warren, J. Chem. Soc., Perkin Trans. 1 1983, 2879.